“Exciting and challenging” were the words Sarah H. “Holly” Lisanby, Director of the Division of Translational Research at the National Institute of Mental Health (NIMH), used to summarize the workshop. She said there is tremendous clinical excitement about what could be a “paradigm shift in psychiatric therapeutics” if psychedelics prove to be fast-acting, highly effective, potentially long-lasting treatments for severe major depressive disorder, posttraumatic stress disorder, substance use disorders, and other psychiatric conditions. Neuroscience researchers also expressed great scientific excitement about novel mechanisms that could lead to rapid responses and rapid therapeutic recovery, said Lisanby. “This could be an opportunity to transform our understanding of the neural origins of illness and recovery and development of new treatments that are potentially faster than what we currently have, our existing drugs that take weeks to work,” she said. Finally, she said, the societal impact of these agents requires further exploration to avoid some of the mistakes of the past 50 years and ensure responsible use, she said.
CLINICAL CHALLENGES FOR PSYCHEDELIC THERAPY
Data from Phase 2 and 3 clinical trials suggest large effect sizes for the treatment of posttraumatic stress disorder (PTSD) and treatment-resistant depression, and the narratives of individuals who have benefited from psychedelic therapy indicate that psilocybin and 3,4-Methylenedioxymethamphetamine (MDMA) enabled them to live full and rich lives free of the crippling effects of their psychiatric disorders, said Lisanby. Yet, she noted that several challenges remain.
The first concern, she said, is the reliability of the reported large effect sizes, which could have been influenced by bias; unblinding of patients, therapists, and raters; patients’ and therapists’ expectations about the benefits of the therapy; placebo effects; and conditioning, which could confound crossover trial designs. Alternative trial designs, such as using active comparators, objective outcome measures, and biomarkers, could help mitigate these challenges, said Lisanby. She also raised concerns about the rigor, reproducibility, and generalizability of these trials, particularly because they were conducted mostly with relatively small sample sizes in self-selected groups of participants and typically exclude people with a history of psychosis or suicide attempts. “This limits knowledge about outcomes in diverse patient groups,” she said.
Related to clinical efficacy, Lisanby mentioned significant knowledge gaps, including the importance of and optimal format for the psychotherapeutic component of treatment, whether the subjective hallucinogenic experience is required to achieve efficacy, the mechanisms of action of these agents, the interindividual variability in response, and safety concerns about the drug itself and the psychosocial context in which the drugs are used. One of the questions about drug safety is whether the powerful neuroplasticity effects could be maladaptive, she said. There are also risks of cardiotoxicity and aversive experiences during treatment, as well as unanswered questions about the abuse potential of these agents, said Lisanby. Safety concerns have also been raised related to the risk of boundary violations and sexual misconduct by providers while patients are in a vulnerable state, she said.
Implementing clinical therapy with psychedelics poses further challenges related to optimal dosing and standardization of provider and therapist training, she said. Dose-response studies that address both the optimal dose range of the drug and the psychotherapy are currently lacking, said Lisanby. Questions also remain about the long-term durability of treatment effects and the minimum amount of psychosocial support needed, which goes to the question of scalability, she said, adding that group therapy sessions could potentially address some of the scalability concerns.
Scientific Impact and Remaining Challenges
An emerging literature base in both humans and animal studies has begun to shed light on the molecular, cellular, and circuit-level mechanisms in different brain regions that underlie the effects of psychedelics, noted Lisanby. Even when the psychogenic and hallucinogenic properties of psychedelics are removed through chemical modifications, structural and functional plasticity and increased dendritic spine growth remain and might mediate therapeutic benefits, though this has yet to be tested in humans she said.
The testimonies of Nora Osowski and Lori Tipton in Chapter 2 emphasized the important role played by therapists during, before, and after drug administration. They cited the meaning they derived from the therapeutic experience as a factor essential to them receiving a beneficial treatment effect. While set and setting continue to be considered essential non-drug elements of psychedelic therapy, evidence on the mechanisms underlying those processes is only correlational at this point, said Lisanby.
Lisanby cited several scientific challenges that can only be answered through additional research. “We need to know more across the board,” she said, from molecular to psychological levels, to understand what is necessary and sufficient to achieve efficacy and ensure safety, she said.
Psychedelics’ Societal Impact: From Counterculture to Therapy
In Chapter 2, Charles Grob described the long history of psychedelics, dating back thousands of years to shamanic cultures and Indigenous peoples. Lisanby noted that as Western medical communities began to explore therapeutic applications of these agents in the 1960s, they seeped out of the medical arena and into the “counterculture movement.” Now, as the medical and scientific communities are again looking toward these compounds as therapeutic interventions, steps are needed to ensure that society is ready for responsible use of these agents, she said. She called for a consensus on terminology and classification of these drugs; an industry ecosystem to develop pharmaceutical grade compounds for research; professional and ethical standards around the conduct and safety monitoring of these agents; methods of accountability around the use of therapeutic touch to protect from boundary violations; and the use of an enhanced consent process to better inform patients of risks and benefits.
To generate safety and efficacy data that will support FDA approval, large, adequately powered, and well-controlled trials are needed, and for both these trials and future clinical treatment, equitable access to diverse communities is essential, said Lisanby. As noted by Charma D. Dudley, Caroline Dorsen, and Dominic Sisti, this will require developing trust across
diverse communities, such as people of color, LGBTQIA+, and people with disabilities, as well as diverse representation among researchers and across all members of interprofessional care teams.
PERSPECTIVES FROM A DIVERSE GROUP OF STAKEHOLDERS
Given the emerging themes as summarized in this chapter, a panel of stakeholders from industry, academia, the federal government, and patient advocacy groups was convened to discuss critical research gaps, potential next steps, and promising opportunities for future action.
The Promise and Peril of Psychedelics
Daniel Karlin, chief medical officer at MindMed, cited both the promise and the peril of psychedelic drugs. The promise would be realized if these drugs lead the field to “return to a psychiatry that is oriented toward cure and recovery” rather than accepting moderate-effect sizes and treatments that help some of the people some of the time, said Karlin. The peril, he said, is that the field fails to get these drugs to people in a reasonable and safe way. “We absolutely have to ensure that there are systems in place so that the folks most in need, the folks left behind by society, are able to access these drugs and get their benefits.”
From the perspective of the federal government, and the Substance Abuse and Mental Health Services Administration (SAMHSA) in particular, the field around psychedelics is currently faced with a unique opportunity, as more people are coming into the field and paying attention to the complex and crucial issues that need to be addressed, said Captain Sean Belouin, a clinical pharmacist with the U.S. Public Health Service. SAMHSA wants to ensure that the best science is guiding decision making and that the use of psychedelics is done responsibly, accountably, safely, and ethically to prevent misuse, he said. He added that preventing misuse is foundational to harm reduction, risk mitigation, and safety monitoring.
Determining the Necessity of Multiple Treatment Elements
Walter Dunn provided the perspective of a clinical trialist, researcher, and clinician. He is an assistant professor of psychiatry at the University of California, Los Angeles, and section chief for mood disorders at the Greater Los Angeles Veterans Affairs Healthcare system. Dunn suggested that it may not be possible to arrive at a point where the elements of treatment can be strictly divided into those that are essential and those that are not. “I think the answer will be, ‘it depends,’” he said. There will be clinical situations where two therapists and 6 hours of preparation are essential for
safety and efficacy, and other situations where one therapist and an hour of preparation will suffice, said Dunn. Rather than a single, one-size-fits-all approach, Dunn envisions multiple validated and well-studied permutations of a treatment model that can be adapted to a diversity of clinical situations.
Dunn further suggested that rather than talking about how these treatment paradigms can be stripped down to make them fit within a broken medical system, the field should be learning from the experiences of psychedelic-assisted therapy and incorporate principles such as psychotherapeutic support into other treatment strategies. “Perhaps it is the therapeutic alliance and the time spent understanding our patients that is at the crux of why these treatments work so well,” he said. To that end, he noted that the real-world application of these treatments in all of their permutations and in a complex patient population provides tremendous learning opportunities for both clinicians and policy makers.
However, Joshua Gordon, director of National Institute of Mental Health (NIMH), said that while there is not good evidence for the need for the different components, there are “good, inherent, moral imperatives” to describe the relative efficacy of each of these components because of safety and availability issues as well as costs to both the patient and the system. There is a moral imperative to study the separate and conjoint effects of these various aspects, he said.
Dunn added that there may also be other psychotherapeutic modalities that combined with psychedelics could achieve similar levels of efficacy and safety. He noted that the types of psychotherapies currently used in the Multidisciplinary Association for Psychedelic Studies (MAPS) or COMPASS protocols may limit the rollout if their approvals specify that treatment is limited to clinicians trained in these specific psychotherapy models. Most clinicians have not been formally trained in the MAPS or COMPASS therapy models, although they are likely to be trained in other therapy modalities, such as cognitive behavioral therapy.
Nora Volkow added that what may be valid for one indication may not necessarily be valid for another. “We have to be more specific in our language,” she said. For example, she said one of the things that happens in addiction is that a person loses the capacity for self-regulation. A mechanism that improves self-regulation, even if it does not affect other neurocircuits, could improve the likelihood of successful recovery in individuals treated for substance use disorder, said Volkow. For other mental illnesses, she suggested determining to what extent targeting certain neurocircuits could be beneficial without necessarily affecting all elements of the experience.
Advancing High-Quality Research
Psychedelics offer hope for a better future for people with mental illness, but their potential will only be realized with more high-quality research, said Shirley Holloway, president of the National Alliance on Mental Illness (NAMI) board of directors. Holloway also endorsed Charles Raison’s call for early intervention. Yet, public perception will play a crucial role in the future use of psychedelics, she said, recalling Thomas Insel and Paul Summergrad’s admonition at the 2017 Psychedelic Science conference that a “single, sloppy, researcher or patient with a disastrous experience would poison the well for everybody.”
Volkow agreed that federal agencies need to accelerate the development of knowledge that can facilitate that translation of “very tantalizing” findings into potential treatments for mental illness; however, she cautioned about losing perspective and creating expectations that are too high, which can lead to increased use. “We have seen that happen with the promise of marijuana as a potential therapeutic for a wide variety of diseases and disorders,” she said.
In terms of research priorities, Volkow said there are some “low-hanging fruits,” such as better characterization of diverse types of drugs that are called psychedelics. She noted that during the COVID-19 pandemic, harmonization of standards emerged as a valuable endeavor and suggested that there are ways to achieve standardization while still allowing flexibility. A major obstacle that slowed down cannabis research and is also likely to slow down psychedelic research was the scaling process, she said. In addition, working with both the Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) will be essential to enable research to move forward on Schedule I substances without having to go through the procedures that are intended for non-research-related drug users. She added that as the director of National Institute on Drug Abuse (NIDA), she cannot ignore the potential of psychedelics for misuse and the need to minimize adverse consequences.
Gordon said that for safety reasons, the most important and controversial question is whether the subjective effects are required for therapeutic action. He acknowledged that there are powerful arguments in support of the hypothesis that subjective effects are inextricably linked to the therapeutic action via neuroplastic effects. “I think it’s a hypothesis we need to test,” he said. Indeed, he added, “there is no such thing as experience without neurobiology.” Even if subjective experiences are essential for treatment effects, those subjective effects are driven by neurobiology, he said.
In support of the idea that subjective experience may be essential, Dunn offered the disease model of posttraumatic stress disorder (PTSD) to highlight the critical role of subjective experience in driving neurobiological
changes and the resulting symptomology and functional impairment. In PTSD, the traumatic event is wholly a subjective distressing experience that is the necessary precipitant leading to a distorted or negative narrative that persists and contributes to depression and patient functional impairment. He suggested that an intense positive valence experience, such as those induced by psychedelics or entactogens, could function in a similar capacity but yield a durable positive narrative that could facilitate recovery from psychiatric illness and improved resilience to future stressors. Investigator-initiated research is critical, said Karlin, but can be hampered by regulations and lack of access to research-grade psychedelic agents. Volkow noted that researchers can obtain Schedule I substances from NIDA and other suppliers, as long as those sources are approved by the DEA. Schedule 1 substances can also be imported from other countries with appropriate DEA approvals, she said.
Promoting Diversity and Ensuring Equity in Research and Care
Volkow reinforced what many other workshop participants have discussed about the need to recruit diverse populations for clinical trials, adding that this will require addressing the unique challenges posed by some minority and underserved groups, including the lack of trust in governmental organizations and health care systems. She added that the economics of these agents should also be incorporated into research models to ensure that these treatments are accessible, equitable, and sustainable. Finally, she suggested that lack of trust may influence the psychedelic experience itself and said this possibility will need to be investigated.
Lisanby noted that, as has been previously discussed in terms of health care justice and equity, trauma runs deep in Indigenous communities, and it is particularly important not to leave these populations behind in the development of psychedelics and entactogens. The challenge, said Holloway, is how to provide high-quality treatment to Indigenous communities. The trauma in these groups has many layers, she said. “It is just layer after layer of issues that need to be addressed in a very thoughtful way, with cultural humility,” she said.
Gordon said the National Institutes of Health (NIH) has several clinical and translational research collaborations with tribal nations and in Alaskan, Indian, and Native American populations in the United States, and is open to other ideas for understanding the use of psychedelic treatments for reducing the impact of trauma in these populations.
Addressing the Mental Health Needs of Military Service Members
Many veterans have suffered serious trauma and moral injury associated with combat, and current therapies are not addressing their needs,
said Belouin. He suggested that psychedelics could be used as part of the biopsychosocial spiritual therapy model, which is used across all hospitals and hospice palliative care networks to treat patients with existential distress and demoralization. This model, he said, involves the entire spectrum of clinical and non-clinical health care practitioners trained in counseling, including physicians, nurses, pharmacists, social workers, licensed counselors, and faith-based practitioners. He encouraged people working in the psychedelic field to broaden their minds in terms of the types of individuals who can support patients receiving treatment. It will require a significant workforce, with interdisciplinary cross-training, credentialing, and licensing, he said.
Dunn added that much of the movement and energy to advance research into psychedelic-assisted therapy has come from veterans, working behind the scenes to influence state legislatures to increase funding in this area. As an integrated health care system, the Department of Veterans Affairs (VA) system also has the potential to be a valuable source of information about safety and efficacy when these treatments are rolled out clinically, said Dunn. He noted that the VA was able to roll out esketamine soon after its approval, getting this new treatment to veterans quickly with an enhanced risk evaluation and mitigation strategy (REMS)–like program, safety parameters, and the systematic collection of data on safety and efficacy. Other managed health care systems could also potentially collect high-level quality data if they choose to roll out novel treatments soon after approval, he said.
The Search for Biomarkers
Given the challenge of confirming efficacy in the absence of placebo controls or other comparators, during the open discussion, Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), suggested that objective efficacy biomarkers might provide a solution. Positron emission tomography (PET) binding of serotonin receptors is clearly a mechanistic biomarker for target engagement, he said, but has not been used as an efficacy biomarker. Volkow noted that PET can also be used to assess receptor occupancy to guide dosing and timing. She added that functional magnetic resonance imagining (fMRI) can provide information regarding a drug’s effect on circuitry, which can be used to predict a response. Because this methodology may be useful in detecting an early signal and for assessing the differences in responses among individuals, she suggested that fMRI may provide an indicator of treatment success.
Lisanby added that FDA has begun to emphasize the importance of patient-reported outcomes in the regulatory pathway. “It is not a biomarker
per se, but is something that transcends diagnosis and really looks at whether [a treatment] is making a difference in the person’s life,” she said. Indeed, said Karlin, because psychiatric illnesses such as major depressive disorder are subjectively defined with no meaningful biological construct, the only way to know what a person is feeling is to ask them.
One potential early “objective” marker of response might be objective changes or subjective improvement in sleep, added Dunn. He said this has been observed in patients who responded to treatment with selective serotonin reuptake inhibitors (SSRIs).
CONCLUDING REMARKS
Sanacora concluded the workshop by reiterating the excitement, optimism, and promise of psychedelics, balancing this against concerns about the complexity, ethics, licensing, regulatory oversight, public health, and health equity issues that need resolution. “The workshop provided a solid platform to launch us into the next phase of research and development in this area,” he said.
